This NIH Mentored Clinical Scientist Research Career Development Award proposal describes a five-year training program for career development in academic cardiovascular medicine. The principle investigator has completed clinical fellowship in Cardiovascular Medicine at Brigham and Women's Hospital and will embark on a research program designed to train for an independent career in disease-oriented research. The principal investigator will acquire in-depth experience in transcription, cell biology, metabolism, lipid chemistry, and analytical approaches to chemistry including mass spectrometry as well as integrated physiologic studies in vivo. Both Dr. Jorge Plutzky and Dr. Alan Saghatelian will mentor the principal investigator's scientific development during this period. Dr. Plutzky is a scientific leader in transcriptional regulation of lipid metabolism and vascular inflammation with an established track record. Dr. Plutzky has mentored other trainees to successful careers in biomedical investigation. Dr. Saghatelian is an established leader in the field of lipid metabolomics and lipid chemistry in the Department of Chemistry, Harvard University. At the interface between chemistry and biology, this career development award creates a unique training environment for the applicant. This comprehensive program described will be further enhanced by collaborations in the research quadrangle and Department of Chemistry. As the primary location for the project, Harvard Medical School/Brigham and Women's Hospital Center for Excellence in Vascular Biology is an exceptional institutional environment providing innumerable resources to assure the principal investigator's success toward an independent career in academic medicine. We provide novel evidence that hepatic lipase selectively activates peroxisome proliferator-activated receptor-4 (PPAR4) transcription in vitro and in vivo through VLDL hydrolysis by generating fatty acid metabolites. This data frames the central hypothesis of this proposal: hepatic lipase selectively activates PPAR4 -dependent transcription that coordinates fatty acid metabolism in the liver. We propose to study the mechanisms and the transcriptional and metabolic consequences of hepatic lipase-mediated PPAR4 activation in vitro and in vivo. The specific aims are: (1) to study the molecular basis of hepatic lipase- mediated PPAR4 activation in vitro;(2) to determine the role of hepatic lipase-mediated PPAR4 activation in transcriptional and functional regulation of hepatocyte fatty acid metabolism. These studies will utilize hepatic lipase gain- and loss-of-function techniques and hepatocyte-specific PPAR4 deficient mice. An understanding of endogenous PPAR4 activation through hepatic lipase action has fundamental implications for the pathogenesis of diseases rooted in metabolic dysfunction including diabetes mellitus and atherosclerosis. PUBLIC HEALTH RELEVANCE: The epidemics of diabetes mellitus and metabolic disorders such as obesity are a major cause of heart disease and death in the Western world. This proposal studies how PPARs, a family of proteins that control metabolism in humans, are regulated. Better insight into how PPARs work will identify new ways to treat metabolic diseases with the goal of improving public health.